The inability of the present therapies to mitigate the devastating effects of sepsis and multiple organ failure in the critically ill patient indicates that more knowledge of the pathophysiology of sepsis is needed if we are to develop better, more effective interventions. In this respect, studies from our laboratory and recently others indicate that blocking the Fas pathway using various approaches, via gene deficiency, fusion protein/antibodies and recently in vivo administration of siRNA, preserves not only splenic immune responsiveness, cardiovascular function, and organ perfusion but also reduces liver damage while improving septic animal survival. However, the nature of Fas/ FasL interactions at a cell-cell as well as an intracellular level in these various tissue sites that lead from apoptosis to organ dysfunction/ damage remain poorly understood. For example, while we have shown that deficiency of CD8 cells or FasL gene expression reduced the incidence septic mouse liver apoptosis, only FasL -/- protected the spleen from increasing apoptosis. In this regards, while ligation of Fas was initially described as driving signaling simply for apoptotic cell death via classic caspase-dependent pathway it is becoming clearer that it signal via activation of a variety of proteins inducing aspects of inflammation and/or programmed necrotic cell death. This characteristic appears to be at least in part a reflection of the given target cell's ability to respond to death receptor signals;thus, possibly explaining how blocking Fas signaling can inhibit not only the onset of apoptosis but aspects of inflammation as well as necrotic cell death/organ damaged encountered in the septic animal. Here we put forward the following hypothesis that the nature of the immune and/or organ dysfunction encountered in the septic rodent/ patient is a reflection of not only the types of cells stimulating/ mediating the response but the varying capacity of the target cell in a given tissue/ organ to perceive these death receptor/ 'extrinsic'stimuli as either an apoptotic, inflammatory and/or necrotic cell stimuli. To examine this hypothesis we have designed the following aims: Aim 1: we will delineate the nature of the cellular components that contribute to the initiation of extrinsic (FasL/ Fas) mediated septic splenic, intestinal and hepatic cell apoptosis, inflammation and/or organ/immune dysfunctions;and Aim 2, we will establish the degree to which signaling via FasL/ Fas induces activation of classic apoptosis as opposed to inducible necrotic cell death in effectors vs. target cells. Data from such studies should provide not only new insight into the pathobiology of sepsis, but also better therapeutic targets for the management of this devastating condition. PUBLIC HEALTH RELEVANCE: The inability of the present therapies to mitigate the devastating effects of sepsis and multiple organ failure in the critically ill patient indicates that more knowledge of the pathophysiology of sepsis is needed if we are to develop better, more effective interventions. This study will examine the concept that the nature of the immune as well as the organ dysfunction encountered in the septic rodent/ patient is a reflection of not only the types of cells stimulating/ mediating the apoptotic response but the varying capacity of the target cell in a given tissue/ organ to perceive these death receptor stimuli as either an apoptotic, inflammatory and/or necrotic cell stimuli. Data from such studies should provide not only new insight into the pathobiology of sepsis, but also better therapeutic targets for the management of this devastating condition.